SUMMARY Norepinephrine is a neurotransmitter thought to be involved in driving behavioral flexibility. It is released by a small number of neurons throughout the neocortex. Little is known, however, about what signals these neurons provide, and how targets in neocortex use those signals, in the context of well-controlled behaviors in mammals. This proposal aims to determine functions of norepinephrine-releasing neurons in the locus coeruleus, the primary source of forebrain norepinephrine. The behaviors to be studied involve different types of flexibility: the ability to switch between using different sensory modalities to select the relevant one for receiving a reward, and the ability to choose among different alternatives that yield reward with changing probabilities. The goal of the project is to link action potentials from identified norepinephrine-releasing neurons to membrane potential, action potentials, and calcium dynamics, in primary somatosensory cortex and prefrontal cortex, in the context of flexible behavior. Three aims test three hypotheses that address different mechanistic questions about the functions of norepinephrine in neocortex: 1) norepinephrine acts in sensory cortex to modulate the perceptual outcome of a sensory stimulus; 2) norepinephrine regulates switching between relevant sensory modalities; 3) norepinephrine and prefrontal cortex activity correlate with dynamic updating of behavior. Simultaneous measurements of activity of norepinephrine neurons and their targets in neocortex, during well-controlled behavioral tasks in mice, will enable testing these three hypotheses. Ultimately, understanding when and where norepinephrine is released in the brain will be necessary to understand flexible behavior in general, and disorders of attention and mood that rely on norepinephrine signaling.